Journal
OPEN BIOLOGY
Volume 6, Issue 11, Pages -Publisher
ROYAL SOC
DOI: 10.1098/rsob.160162
Keywords
biofilms; c-di-GMP; rough small colony variants; reactive oxygen species; Pseudomonas aeruginosa; adaptive evolution
Categories
Funding
- National Research Foundation
- Ministry of Education of Singapore under its Research Centre of Excellence Program
- Nanyang Technological University [M4330002.C70]
- AcRF from Ministry of Education, Singapore [MOE2014-T2-2-172]
- Lee Kong Chian Medicine Postdoctoral Fellowship
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The host immune system offers a hostile environment with antimicrobials and reactive oxygen species (ROS) that are detrimental to bacterial pathogens, forcing them to adapt and evolve for survival. However, the contribution of oxidative stress to pathogen evolution remains elusive. Using an experimental evolution strategy, we show that exposure of the opportunistic pathogen Pseudomonas aeruginosa to sub-lethal hydrogen peroxide (H2O2) levels over 120 generations led to the emergence of probiofilm rough small colony variants (RSCVs), which could be abrogated by L-glutathione antioxidants. Comparative genomic analysis of the RSCVs revealed that mutations in the wspF gene, which encodes for a repressor of WspR diguanylate cyclase (DGC), were responsible for increased intracellular cyclic-di-GMP content and production of Psl exopolysaccharide. Psl provides the first line of defence against ROS and macrophages, ensuring the survival fitness of RSCVs over wild-type P. aeruginosa. Our study demonstrated that ROS is an essential driving force for the selection of pro-biofilm forming pathogenic variants. Understanding the fundamental mechanism of these genotypic and phenotypic adaptations will improve treatment strategies for combating chronic infections.
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